Biomedical subjects
Publications and source records attributed to H D Thames.
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PURPOSE: While tumor volume is an important parameter predicting clinical outcome, its relationship to clonogen number remains uncertain. This uncertainty is related to many factors, among them treatment response heterogeneity, which obscures the influence of patients and treatment-related parameters. In this study, we analyze the effect of tumor volume on local and regional recurrence in a setting tightly controlled for dose, treatment time, and patient selection. The hypothesis that changes in clonogen number scale directly with changes in tumor volume is tested. METHODS AND MATERIALS: Using digital reconstruction of diagnostic computed tomography (CT) scans, primary and total tumor volumes were estimated in 51 cases of advanced squamous cell carcinoma of the head and neck. All patients were managed with a concomitant boost accelerated superfractionated schedule to a median dose of 70.2 Gy. Clinical data were fitted to a mixture model to relate tumor volume parameters to control probability where volume and clonogen number were related by the relationship m = a.Vb, where m is initial clonogen number, a is a proportionality constant, V is tumor volume, and b is the volume exponent. RESULTS: Tumor volume estimates for primary tumor ranged from 3-196 cm3 and for total tumor volume 5-196 cm3. Actuarial local-regional control is 63%. The estimated volume exponent b is 0.85 (95%, confidence interval (c.i.): 0.40-1.29) for primary tumor volume and 1.1 (95%, c.i.: 0.33-1.85) for total tumor volume. CONCLUSION: This study quantifies the adverse influence of tumor volume on local-regional disease control in advanced head and neck cancer. The derived volume exponent approximates to one, the theoretical expectation if the growth fraction is roughly constant and clonogen number increases linearly with volume. Finally, these results suggest that radiobiological parameters are more reliably estimated from clinical data with narrowly defined strata.
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The radiation dose-survival of various hematopoietic cell subsets in murine bone marrow (BM) was determined in the cobblestone area forming cell (CAFC) assay under conditions of single-, split-, and multiple-dose irradiation. A greater recovery in cell survival with decreasing dose per fraction, or increasing fraction number, was observed for primitive CAFC day-28 and day-35 than for CAFC day-6 and day-12 (colony-forming unit (CFU)-granulocyte macrophage and CFU-spleen day-12 equivalents). Linear quadratic (LQ) model analysis of CAFC survival data provided an estimate of the alpha/beta ratio that is an inverse index of the fractionation effect and is known to be lower for late than for acutely responding tissues. This analysis gave decreasing alpha/beta ratios with increasing primitiveness of the CAFC subset. These values were found to be comparatively low (about 4 Gy) for CAFC day-28 and day-35 and are in general agreement with previous studies on long-term repopulation in vivo. In contrast, alpha/beta ratios of CAFC day-6 and day-12 were relatively high (above 6 Gy) and are consistent with values obtained from acute marrow failure. Delayed harvesting of BM after a single dose of 6 Gy showed little evidence of proliferative repopulation over 1 week and hence the differential dose-sparing effect of fractionation among the CAFC subsets appears to be mostly attributable to the influence of sublethal damage repair. These results require a reevaluation of previous notions of marrow stem cell radiosensitivity and repair based on acute marrow lethality (LD50/30) or spleen colony (CFU-S) data, especially when applied to fractionated total body irradiation effects on long-term repopulating stem cells in a BM transplant setting.
PURPOSE: The morphologic responses of the monkey kidney glomeruli and tubules to fractionated irradiation were assessed. METHODS AND MATERIALS: Both kidneys of adult female rhesus monkeys were irradiated with doses of gamma-rays ranging from 24 Gy in 12 fractions up to 36 Gy in 18 fractions. Serial renal biopsies were taken between 1 and 12 weeks after irradiation. The kidneys were removed at necropsy 16-23 weeks after irradiation. Glomeruli were assessed for the presence of pathologic features, including intercapillary eosinophilic material, ectatic capillaries, thrombi, hemorrhage, adhesions, and sclerosis. The relative proportion of renal cortex occupied by glomeruli, interstitium, or tubules was determined using a Chalkley point grid. Tubules were further scored as being either normal or abnormal in appearance. RESULTS: Examination of the renal biopsies revealed that progressive glomerular lesions were evident within 4-12 weeks after irradiation. Tubular changes were mild and focal. Morphometric analysis of whole kidneys removed at necropsy demonstrated that numbers of glomeruli with ectatic capillaries, thrombi, and hemorrhage were significantly different from controls at 16-23 weeks after irradiation by all of the doses in the range of 24 to 36 Gy. A significant (p < 0.05) increase in the relative proportion of renal cortex occupied by glomeruli and interstitium was indicative of tubule loss. Further analysis of these tubular changes revealed a highly significant (p < 0.001) dose-dependent increase in the proportion of abnormal to normal tubules. Thus following a dose of 24 Gy in 12 fractions, the ratio of abnormal: normal tubules was approximately 1:2; after 36 Gy in 18 fractions the ratio was 3:1. CONCLUSIONS: Glomeruli appeared to be very radiosensitive because after the clinically relevant dose of 24 Gy in 12 fractions essentially all glomeruli were altered in the irradiated kidneys as compared to controls. Thus, efforts aimed at increasing the threshold dose for development of radiation nephropathy should be directed primarily at preventing the glomerular lesions.
PURPOSE: to estimate the alpha/beta ratio for damage to human lung after thoracic irradiation for Hodgkin's disease. PATIENTS AND METHODS: The criterion for lung injury was the presence of radiological changes in the vicinity of the mediastinum as assessed on regular follow-up chest X-ray examinations. Patients with supradiaphragmatic stage I-II Hodgkin's disease received mantle field irradiation as part of their treatment between 1964 and 1981 (E.O.R.T.C. protocols H1, H2, and H5). The total mediastinal doses fixed by the protocols were 35-40 Gy. The fractional doses were left to the decision of the physicians in charge: the most frequent regimens were 5 x 1.8, 5 x 2.0, 4 x 2.5 and 3 x 3.3 Gy per week. The data were fit to the linear-quadratic (L.Q.) model using time-to-injury as endpoint. RESULTS: 1048 (97%) of 1082 patients were evaluable. The mean follow-up duration was 8 years. One hundred and ninety-five cases of radiologically-visible lung damage were observed after a median interval of 6 months (range: 0-101). The 3-year actuarial probability of lung damage was 19% (95% confidence limits: 17, 21). Multivariate analysis (Cox model, stratified by protocol) showed an increased risk of damage with dose per fraction (relative risk, R.R. = 2.22 per Gy (1.75, 2.82)), the presence of systemic symptoms (R.R. = 1.53 (1.09, 2.15)), and total mediastinal dose (R.R. = 1.06 per Gy (1.01, 1.12)). Age, sex, histological type, number of involved nodal sites and radiotherapy duration did not significantly modify the risk of lung damage. The L.Q. model parameters were: alpha = 0.031 Gy-1 (0.003, 0.059), beta = 0.010 Gy-2 (0.007, 0.013), alpha/beta = 3.07 Gy (-0.23, 8.46). CONCLUSION: this low alpha/beta ratio is consistent with late effects values from animals and humans, and illustrates the influence of large fraction sizes on the occurrence of late pulmonary complications.
Data published previously have shown that repair of sublethal damage in mouse lung proceeds with two significantly different repair half-times of 0.4 h and 4.0 h and that the fast component has approximately four times more weight than the slow component. None of these data, however, were obtained after small dose fractions similar to those used in clinical radiotherapy. The purpose of the experiments presented here was to determine the half-time of the fast component only of repair in mouse lung after doses per fraction of 2.0 Gy. We irradiated the whole thoraces of mice with six equal doses of 2.09 Gy given at intervals ranging from 0 to 45 min. The dose was topped up 24 h later by a range of single doses designed to bring the response, i.e. breathing rate and death from pneumonitis, into the observable range. Data on breathing rate were converted into quantal response data. All data were analyzed by the linear-quadratic model that contains two rates of repair (H.D. Thames et al., Radiother, Oncol. 15, 49-53, 1989). The data showed that the repair rate is very rapid, giving a t1/2 ranging from 0.25 to 0.75 h for breathing rate and mortality, in agreement with our data published previously for higher dose fractions. There were no differences between the t1/2's obtained from the two assays of damage. These data indicate that the half-time of the fast component of repair in mouse lung is approximately 0.4 h after clinically relevant dose fractions.
PURPOSE: The long-term functional and morphologic responses of the hypertrophied monkey kidney after unilateral nephrectomy to fractionated irradiation were assessed. METHODS AND MATERIALS: The right kidney of 13 adult female rhesus monkeys was removed. Twelve weeks after unilateral nephrectomy (UN) the remaining kidney received fractionated doses of gamma-rays ranging from 35.2 Gy/16 fractions (F) up to 44 Gy/20 F. Glomerular filtration rate, effective renal plasma flow, blood urea nitrogen, serum creatinine, and hematocrit values were measured up to 107 weeks postirradiation (PI). The monkeys were killed and the remaining kidneys were removed 107 weeks PI or earlier when end-stage renal failure was exhibited. Glomeruli were scored for the presence/absence of several pathologic features including increased intercapillary eosinophilic material (ICE), ectatic capillaries, and thrombi. The relative proportion of renal cortex occupied by glomeruli, interstitium, normal tubules or abnormal tubules was determined using a Chalkley point grid. These quantal dose response data were analyzed using a logistic regression model. RESULTS: Irradiation of the remaining kidney in UN monkeys resulted in a dose-dependent reduction in renal function and anemia. Glomerular dysfunction preceded tubular dysfunction. Animals receiving 44 Gy all manifested progressive clinical renal failure. Conversely, those receiving < or = 39.6 Gy showed stable, albeit impaired, renal function for the duration of the observation period of 107 weeks. Morphologically, the incidence of ICE, ectatic glomerular capillaries, thrombi, and periglomerular fibrosis was significantly dose-related (p < 0.005). A significant (p < 0.001) dose-related increase in the relative proportion of renal cortex occupied by abnormal tubules was indicative of tubular injury. A highly significant (p < 0.001) dose-dependent increase in the proportion of abnormal to normal tubules was also seen. CONCLUSION: The pathogenesis of radiation nephropathy is difficult to fully understand because of the complex and dynamic interactions among all components of the nephron that make discrimination between primary radiation effects and secondary pathophysiological consequences very difficult. Notwithstanding, the current experiment shows that the functional and morphological expressions of radiation injury in the kidney are dose dependent. Renal failure occurs when both the glomeruli and tubules are dysfunctional. In monkeys following UN, a total dose of 44 Gy to the remaining kidney damages all components of the nephron and causes renal failure in less than 45 weeks. With lower doses, changes to the glomeruli predominate and the animals survive. Kidney doses of up to 39.6 Gy/18 fractions of 2.2 Gy are compatible with survival for at least 2 years in primates.
PURPOSE: Recent studies of human cell lines cultured in vitro and mathematical modeling of the response of acute and late responding tissues have predicted conditions for the equivalence in terms of cell killing of continuous and pulsed dose rate brachytherapy. The aim of this study was to test these predictions in vivo using an acutely responding normal tissue. METHODS AND MATERIALS: The microcolony assay was used to quantify the survival of jejunal stem cells in vivo. Mice were exposed to graded doses of 60Co delivered continuously or as 1- or 10-min pulses given once-per-hour at an average dose rate of 0.7 Gy/hr. In both cases the total dose-per-hour was 0.7 Gy. Overall exposure times ranged between about 30 and 60 h. Mice were sacrificed 3.5 days after exposure, the bowel removed for routine histological preparation, and number of surviving crypts quantified microscopically. RESULTS: An average dose-per-hour of 0.7 Gy, a pulse width of 10 min, and a pulse frequency of 1 h resulted in biological equivalence of pulsed to continuous treatment. Delivering the pulse in a period of 1 min at a dose rate 10-fold higher resulted in a modest 3-4% shift in the survival curve to lower isoeffective doses. The slopes of the survival curves as described by D(o) values were similar for all treatment regimens tested. CONCLUSION: This in vivo study validates the prediction of biological equivalence between pulsed and continuous brachytherapy at a clinically relevant average dose rate and may generate further interest in this new treatment modality because of its advantages in radiation protection, dose optimization, and cost relative to standard low dose rate brachytherapy techniques.
PURPOSE: Analysis of four different sets of experiments performed by the G.S.F. group in Munich investigating the late tolerance of the rat rectum to external or intracavitary irradiation. MATERIAL AND METHODS: The endpoint was late rectal stenosis in female Wistar rats. The raw data were fitted to the linear-quadratic model by means of a likelihood maximization method (Direct Analysis). The model was altered to allow for repopulation, incomplete repair, and varying irradiated lengths of the rectum. RESULTS: Fractionation sensitivity was high or intermediate (alpha/beta ratio values [95% confidence limits] ranging from 2.67 [0.86, 4.80] to 6.65 [2.21, 11.73] Gy). Significant repopulation occurred when treatments were longer than 5 days (Dprolif equal to 0.61 [0.20, 1.47] and 1.08 [0.58, 1.90] Gy/day, in fractions of 4 Gy). Another interpretation is that radiosensitivity changed during treatment. Repair half-time estimates ranged between 1.84 [1.52, 2.34] and 5.02 [2.83, 21.7] h. Finally, the present analysis indicated that the smallest surviving compartment capable of tissue rescue was about 1/50 to 1/100 of a 1 cm high cylinder of the rectum wall. CONCLUSIONS: The radiobiological features of late stenosis in the rats are consistent with combined injuries of early and late responding components of the rectal wall. This raises some concerns about the possible danger of hyperfractionated treatments, where the beneficial impact of fraction size reduction may be obviated for interfraction intervals that are too short. Also, accelerated irradiation may result in more late complications because of increased early reactions.
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Reactions of the skin of the right thigh of mice were used as an experimental model to test possible changes in the radiosensitivity of mouse skin, as represented by changes in the linear-quadratic (LQ) model parameters alpha and beta, as a function of fractionation interval and overall treatment time. In the first series of experiments, variable numbers of 3-Gy fractions with intervals of 6, 24 or 48 h were applied, followed by top-up doses to increase the skin damage to a level that could be scored. The results showed that mouse skin is more sensitive to 3-Gy fractions applied with 48-h intervals than to 3-Gy fractions applied with 6- or 24-h intervals. In the second series of experiments we used single-dose or fractionated test treatments for previously unirradiated mice and mice treated with priming doses of 10, 20 or 30 Gy given 1-18 days before the test treatment. The sensitivity appeared to be higher after intervals of 14-18 days than after 1-10 days after priming treatments of 20 and 30 Gy. The increased sensitivity 18 days after 20 Gy was mainly the result of an increase in the beta component of the LQ model; higher values of alpha were also determined. We conclude that the radiosensitivity of mouse skin is higher during a radiation-induced proliferative response.
Forty-four eyes in 38 children were treated between 1963 and 1991 by external radiotherapy for retinoblastoma. Treatment modalities varied widely during this period; in addition to radiotherapy there was chemotherapy (16/44), photocoagulation (14/44), and laser therapy or cryotherapy (14/44). Treatment technique and dose fractionation also varied widely; lateral beam technique (39/44) versus anterior or anterior/lateral beam; doses per fraction ranged from 1 to 4.5 Gy, total doses from 30 to 61.5 Gy, and overall times from 22 to 49 days. Patients were followed at 3-month intervals, and actuarial survival at 10 years was 88%, with 62% local control. Ten eyes showed clinical evidence of retinopathy. A multivariate analysis of factors associated with increased risk of retinopathy was carried out using the Cox proportional hazards model and the mixture model of Farewell. The estimated latent time was 17 months (95% confidence interval, 14-20 months). The only factors found to be significantly associated with retinopathy were total dose multiplied by dose per fraction, or total dose normalized to the equivalent total dose in 2-Gy fractions as estimated from the LQ model, and these gave equivalent descriptions. There were trends (not significant) for increased risk of retinopathy when treatments included chemotherapy or photocoagulation, and for decreased risk (also not significant) when cryotherapy was used in conjunction with radiotherapy. No significance could be attached to any of the following: number of sites per eye, Reese-Ellsworth stage, and family history. We conclude that hypofractionation carries a significant risk for retinopathy in the treatment of retinoblastoma.
PURPOSE: to assess mouse rectum tolerance to fractionated X-ray and neutron irradiation. MATERIALS AND METHODS: doses per fraction ranged between 0.25 and 35 Gy for X-rays, 0.05 and 12 Gy for neutrons. Neutron top-up doses were added when the fractionated irradiation was given in fractions less than 2 Gy of X-rays or 0.35 Gy of neutrons in order to bring the damage into the detectable range. The early endpoints were the nadir of weight loss occurring within the first 2-3 weeks following irradiation and lethality by 2 months. The late endpoints were the peak of weight reached at maturity of the mice, the proportion of short feces in the daily fecal output at 10 months and lethality by 12 months. The linear-quadratic (LQ) model was fitted to the data (direct "one-step" analysis) and the estimated parameters were used to calculate relative biological effectiveness (RBE) values. RESULTS: alpha/beta ratio estimates were for X-rays: 19.9 Gy [95% confidence limits: 15.2, 27.0] for weight nadir. 13.4 Gy [9.3, 19.5] for early lethality, 6.4 Gy [3.6, 11.0] for peak weight, and 6.9 Gy [4.2, 10.8] for late lethality, for neutrons 19.9 Gy [9.5, 61.0] for peak weight. The fecal-deformity data were poorly fitted by the LQ model. The RBE was slightly higher for acute endpoints than for the late ones when X-ray fraction sizes were equal to or larger than 10 Gy. However, the change in RBE with decreasing X-ray dose per fraction was much steeper for the late endpoints, so that it became equal to or even higher than for acute reactions at doses per fraction of 5 Gy or less. CONCLUSION: Our results were consistent with those obtained from previously published studies using the same experimental system but larger doses per fraction.
In a previous analysis of node failures in 1251 consecutive patients with node positive oropharyngeal and pharyngolaryngeal squamous cell carcinomas treated by external radiotherapy alone at the Institut Curie, the main reasons for patient exclusion were node recurrence associated with primary failure (N+T failures) and doses less than 55 Gy. These exclusions reduced the number of node failures from 399/1251 (32%) to 77/798 (10%). Multivariate analysis of node recurrence indicated that node size and fixity, treatment duration, and T stage of primary were significant (higher probability of isolated node failure for the T1-T2 primaries). In the present analysis, it is noted that 60% of the N+T failures were observed less than 1 month after the completion of the irradiation and, therefore, were not likely the result of reseeding from the primary tumor. When all 1251 patients were included in the analysis, the probability of nodal failure increased for larger nodes, T4 primaries, lower nodal doses, presence of contralateral node metastases, and nodal fixation to the surrounding structures. No influence of the primary site was found. Treatment duration was closely associated with total dose to the nodes. The best description of the data was obtained with a model including total dose and not treatment time. However, as in the previous analysis, the exclusion of low-dose (less than 55 Gy) treatments resulted in the loss of a significant dose-control relationship. We conclude that the majority of node failures is unlikely to result from reseeding from the primary tumor, and therefore should not be excluded from local-control analyses. From a more radiobiological point of view, the exclusion of palliative treatments is questionable when studying the effect of dose on local control.
Fractionated and low-dose-rate total-body irradiation (TBI) were compared with single-dose high-dose-rate TBI for induction of long-term hemopoietic chimerism in a murine syngeneic bone marrow transplantation model. At 5 months after TBI and bone marrow transplantation, the degree of stable blood chimerism was determined from the proportion of stem cell-derived donor (B6-Gpi-1a) and host (B6-Gpi-1b) blood erythrocytes. This end point was used to construct radiation dose-response curves for long-term donor marrow engraftment corresponding to ablation of primitive bone marrow stem cells of the host. Increasing dose fractionation and decreasing dose rate had the effect of restoring host hemopoiesis and required higher TBI doses for equal donor engraftment. Most of the dose recovery occurred within the first 6 h between fractions, consistent with the kinetics of sublethal damage repair. The late chimerism data were fitted to the linear-quadratic model using indirect and direct analysis for a fixed threshold response. Both analyses gave relatively low alpha/beta ratios (below 2 Gy), within the range normally seen in late-responding tissues. The dose-rate data gave a repair half-time of 2 h as estimated by the incomplete-repair model. These estimates contrast with the much higher alpha/beta values and lower repair half-times derived from acute hemopoietic failure as indicated by LD50/30, with the implication that separate target cell populations with differing radiosensitivities are involved in these two bone marrow end points.
A reanalysis was performed of the extensive data set obtained with fractionated irradiations of mouse lung reported by Travis et al. (Int. J. Radiat. Biol. 52, 903-919, 1987). The possibility was investigated that the poor fit of these data to the linear-quadratic model might have been the result of the presence of two rates of repair of sublethal damage instead of one. Therefore, the incomplete-repair linear-quadratic model was adapted to incorporate two independent rates of repair and the data were analyzed using this two-component incomplete-repair model. The results which are subjected to certain qualifications with respect to the assessment of the validity of the confidence limits indicated the presence of two significantly different repair rates, corresponding to a fast-repair half-time (t1/2) of 0.40 h (0.28, 0.53) and a slow t1/2 of 4.01 h (1.55, 6.57). A weight factor determined simultaneously indicated that the fast component has approximately four times more weight than the slow component. The alpha/beta value calculated for the entire data set using the same model was 3.8 Gy (3.0, 4.6), which is not significantly different from the alpha/beta of 3.6 Gy (2.8, 4.5) calculated for the 8- and 12-h data only, using the complete-repair linear-quadratic model. An experiment specifically designed to test the significance of the fast-repair component was performed in which mouse lungs were irradiated with two equal dose fractions, separated by intervals ranging from 10 min to 6 h. Data obtained from this experiment allowed only one repair rate to be determined, corresponding to a t1/2 of only 0.4 h. This finding confirms the presence of a very fast repair rate in mouse lung.